Biphenyl compound selective agonists of gamma RAR receptors

ABSTRACT

Biphenyl compounds having the formula (I): 
                         
are useful for preventing/treating pathologies linked to a deficiency of the activation of the RAR gamma receptor, e.g., for treating a pathology linked to a cell differentiation and/or proliferation disorder, for treating acne, for treating psoriasis.

CROSS-REFERENCE TO COMPANION APPLICATION

Copending U.S. patent application Ser. No. 12/213,177, filedconcurrently herewith, hereby expressly incorporated by reference andalso assigned to the assignee hereof.

CROSS-REFERENCE TO PRIORITY/PCT APPLICATIONS

This application claims priority under 35 U.S.C. §119 of FR 0512762,filed Dec. 15, 2005, and is a continuation of PCT/EP 2006/068975, filedNov. 28, 2006, and designating the United States (published in theFrench language on Jun. 21, 2007, as WO 2007/068579 A1; the title andabstract were also published in English), each hereby expresslyincorporated by reference in its entirety and each assigned to theassignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the therapeutic administration, inparticular in the dermatology field, of novel biphenyl compoundssubstituted with an aromatic radical having selective activity for thegamma subtype of the RAR receptor family.

2. Description of Background and/or Related and/or Prior Art

A family of biphenyl compounds has been described in WO 99/10308. Thesecompounds are described as having an application in the topical andsystemic treatment of dermatological conditions linked to akeratinization disorder, and of opthalmological conditions inparticular.

The activity of these compounds has in particular been demonstrated bymeans of tests for differentiation of mouse embryonic teratocarcinoma F9cells and keratinocyte differentiation tests in humans.

On the other hand, this publication in no way makes any reference to apossible specific activity of the compounds with respect to the gammasubtype of RAR receptors.

Indeed, the gamma subtype of the RAR receptor family is largelypredominant in the epidermis, where it is approximately 90% of the totalreceptors (“Retinoic acid receptors and binding proteins in human skin”,Elder J T, Astrom A, Pettersson U, Tavakkol A, Krust A, Kastner P,Chambon P, Voorhees J J: J. Invest Dermatol., 1992; 98 (6 Suppl): 36S-41S; or “Retinoic acid receptor expression in human skin keratinocytes anddermal fibroblasts in vitro”, Redfern C P, Todd C., J. Cell Sci., 1992;102 (Pt 1): 113-21), and it is indeed the interaction with this RARgamma receptor which is responsible for the effectiveness of retinoidson the epidermis (“Retinoic acid receptor gamma mediates topicalretinoid efficacy and irritation in animal models”, Chen S, Ostrowski J,Whiting G, Roalsvig T, Hammer L, Currier S J, Honeyman J, Kwasniewski B,Yu K L, Sterzycki R, et al., J. Invest Dermatol., 1995; 104 (5):779-83).

RAR gamma receptors are therefore the sole target in the treatment ofpathologies at the epidermal level, for instance for acne or psoriasisor any other skin pathology treated with retinoids.

Furthermore, certain side effects specific to RAR alpha or RAR beta canbe avoided if compounds having a selective action on RAR gamma are used.

SUMMARY OF THE INVENTION

It has now surprisingly been shown that the compounds according to theinvention have an extremely advantageous selective agonist activity forthe gamma subtype of the RAR receptor family.

The compounds according to the invention, selective agonists of the RARgamma subtype, thus make it possible to prevent and/or treat variousdermatological pathologies or disorders, while at the same timedecreasing the side effects normally caused by the action of the activeagents on the RAR alpha and beta subtypes.

The present invention therefore features compounds having the followinggeneral formula:

in which R is a hydrogen or a hydroxyl radical, and also the salts ofthe compounds of formula (I).

The term “pharmaceutically acceptable salt” means in particular analkali metal salt, or an alkaline-earth metal salt, or an organic aminesalt.

According to a preferred embodiment, the compounds of formula (I) areselected from4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid and4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.

The present invention also features the formulation of at least onecompound of formula (I), into pharmaceutical or cosmetic compositionsuseful in preventing and/or treating pathologies for which a selectiveagonist activity for the gamma subtype of the RAR receptor family isdesired.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE of Drawing is a reaction scheme illustrating preparation ofthe compounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

A general synthetic pathway for preparing the compounds of formula (I)is represented in the scheme shown in the FIGURE of Drawing.

The starting materials and/or the reactants employed are commerciallyavailable and/or can be prepared according to known methods in theliterature.

According to another embodiment, the present invention also features aprocess for preparing the compounds of formula (I) described above,comprising the following steps:

i) coupling reaction, preferably of Suzuki reaction type, from thecompound of formula 1 prepared, for example, as described in WO99/10308:

and the compound of formula 2 prepared, for example, as described in WO99/10308:

to produce the compound of formula 3

ii) reaction of the phenol function of the compound of formula 3 withtriflic anhydride ((CF₃CO)₂O), according to methods known in theliterature (see, for example, Kotsuki H. et al., Synthesis, 1990, (12),1145-1147 or Prince P. et al., Synlett, 1991, (6), 405-406), to producethe compound of formula 4,

iii) reaction, of Stille coupling type, of the compound of formula 4with allyl tri-n-butyl tin (CH₂═CH—CH₂—SnBu₃) according to methods knownin the literature (see, for example, Tilley J. W. et al., J. Org. Chem.,1990, 55(3), 906 or Saa J. M. et al., J. Org. Chem., 1992, 57(2),678-685), to produce the compound of formula 5,

iv) hydration of the allylic double bond of the compound of formula 5,for example by a conventional hydroboration reaction followed byoxidation, according to methods known in the literature (see, forexample: Liotta R., Brown H. C., J. Org. Chem., 1977, 42, 28-36 or LuoF. T., Negishi E., J. Org. Chem., 1983, 48, 5144) or dihydroxylation ofthe allylic double bond of the compound of formula 5 according tomethods known in the literature (see, for example: Corey E. J. et al.,Tetrahedron Lett 1984, 25 (44), 5013, Sharpless K. B. et al., J. Am.Chem. Soc., 1976, 98 (7) 1986), to produce the compounds of formula 6,with, respectively, R═H and R═OH:

v) saponification of the ester function of the compound of formula 6, toproduce the compound of formula (I) (compound 7 in the FIGURE ofDrawing) in which R is a hydrogen or a hydroxyl radical.

Step i) may, for example, be carried out in the presence of potassiumcarbonate and of tetrakis(triphenylphosphine)palladium in a toluenesolution.

Step ii) may, for example, be carried out in the presence oftrifluoromethanesulfonic anhydride and of a base such as triethylaminein an aprotic solvent such as dichloromethane.

Step iii) may, for example, be carried out in the presence of apalladium catalyst such as, for example,bis(triphenylphosphine)palladium chloride (PdCl₂(PPh₃)₂) or elsetris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃) in a polar solventsuch as, for example, dimethylformamide.

Step iv) may, for example, be carried out in the presence of catalyticosmium tetraoxide and of an oxidant such as, for example,N-methylmorpholine N-oxide. As indicated above, in this case, thereaction produces the compound 6 in which R is the hydroxyl radical.

Alternatively, step iv) may also be carried out in the presence of aborane such as, for example, 9-borabicyclo[3.3.1]nonane (9-BBN) followedby oxidation using, for example, aqueous hydrogen peroxide. In thiscase, the reaction produces the compound 6 in which R is hydrogen.

Step v) may, for example, be carried out in the presence of sodiumhydroxide and of THF.

The present invention also features administration of the compounds offormula (I) as described above, as a medicament.

According to another embodiment, this invention features pharmaceuticalor cosmetic compositions, comprising, formulated into a pharmaceuticallyor cosmetically acceptable carrier, at least one compound of formula(I).

The term “pharmaceutically or cosmetically acceptable carrier” means acarrier suitable for use in contact with human and animal cells, with notoxicity, irritation, undue allergic response, and the like, andproportional to a reasonable advantage/risk ratio.

The administration may be carried out topically, enterally or orally,parenterally or ocularly, whether regime or regimen. Among these routesof administration, topical administration is particularly preferred.

When administered topically, the pharmaceutical compositions accordingto the invention are more particularly useful in the treatment of theskin and mucous membranes and may be in liquid, pasty or solid form, andmore particularly in the form of salves, creams, milks, ointments,powders, impregnated pads, syndets, solutions, gels, sprays, mousses,suspensions, sticks, shampoos or washing bases. Same may also be in theform of suspensions of lipid or polymeric vesicles or microspheres ornanospheres, or polymeric or gelled patches for controlled release.

The compounds are employed topically at a concentration generally offrom 0.001% to 3% by weight, relative to the total weight of thecomposition.

For cosmetic applications, the compositions are preferably in the formof a cream, a milk, a lotion, a gel, lipid or polymeric vesicles ormicrospheres or nanospheres, a soap or a shampoo.

When administered enterally or orally, the compositions may be in theform of tablets, gel capsules, sugar-coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, or suspensions oflipid or polymeric vesicles or microspheres or nanospheres forcontrolled release. When administered parenterally, the compositions maybe in the form of solutions or suspensions for perfusion or forinjection.

The compounds according to the invention are generally administered at adaily dose of approximately 0.01 mg/kg to 30 mg/kg of body weight, takenin 1 to 3 doses.

The compounds of the invention can be formulated, alone or as a mixture,into pharmaceutical compositions useful in the treatment and/orprevention of pathologies linked to a deficiency in the activation ofthe RAR gamma receptor.

This invention also features a method of therapeutic or cosmetictreatment, comprising the administration of a pharmaceutical or cosmeticcomposition comprising at least one compound of formula (I), saidcompound exercising a selective agonist activity for the RAR gammareceptor.

The pharmaceutical compositions may be more particularly useful intreating a pathology for which the treatment requires a selectiveagonist activity for the RAR gamma receptor, more particularly at thelevel of the epithelial tissues, the skin and the bones.

The compositions can in particular be administered for the treatment ofa pathology linked to cell differentiation and/or proliferationdisorders, in particular in the dermatology field.

More particularly, same are useful in the treatment of a pathologylinked to a keratinization disorder.

The treatment of acne is thus envisioned, in particular common acne,comedone acne, polymorphic acne, nodulocystic acne, acne conglobata,senile acne, secondary acne such as solar acne, acne medicamentosa oroccupational acne.

The pharmaceutical compositions comprising a compound of formula (I) arealso useful in the treatment of other dermatological conditions linkedto a keratinization disorder with an inflammatory and/or immunoallergiccomponent, and in particular all forms of psoriasis, whether cutaneous,mucosal or ungula.

The compounds according to the invention can also be formulated intocosmetic compositions, for combating skin aging, whether for examplephotoinduced or chronological, or else for the treatment of skin with anacneic tendency of for combating the greasy appearance of the skin orthe hair.

The pharmaceutical or cosmetic compositions are also useful to regulateskin pigmentations and to treat actinic keratoses.

In all the applications envisioned, said compound may be combined withanother therapeutic agent that can be used in the treatment of apathology linked to cell differentiation or proliferation disorders.

As therapeutic agents that can be included in the compositions accordingto the invention, exemplary are agents for modulating skindifferentiation and/or proliferation and/or pigmentation, such asretinoic acid and its isomers, retinol and its esters, retinal,retinoides, estrogens, anti-bacterial agents, antibiotics,anti-parasitic agents, anti-fungal agents, steroidal or non-steroidalanti-inflammatory agents, anesthetics, anti-pruriginous agents,anti-viral agents, keratolytic agents, free-radical scavengers,anti-seborrheic agents, anti-dandruff agents, anti-acne agents, agentsfor combating hair loss, and vitamin C and its derivatives, with theproviso, as is indicated above, that the active agents be in solubilizedform in the composition according to the invention.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative. Insaid examples to follow, all parts and percentages are given by weight,unless otherwise indicated.

In the examples hereinafter, the samples were analyzed by ¹H NMR, ¹³CNMR and HPLC/MS.

Example 1 Synthesis of4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid

a) Preparation of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

10 g (31 mmol) of ethyl 3′-bromo-4′-hydroxybiphenyl-4-carboxylate(prepared according to EP-952,974), 8.7 g (37 mmol) of6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene)boronic acid(prepared according to EP-952,974) and 34 ml (74.6 mmol) of a 2M aqueoussolution of potassium carbonate are placed in 200 ml of toluene, in athree-necked flask, and then 1.8 g (1.55 mmol) oftetrakis(triphenylphosphine)palladium are added under nitrogen. Thereaction mixture is heated for 24 h at 110° C. After cooling, thereaction is stopped by adding 200 ml of water and then extracted withethyl acetate. The organic phases are combined, washed with a saturatedsolution of sodium chloride and dried over magnesium sulfate. Thesolvents are evaporated off and the residue is then purified by silicagel chromatography (80/20 heptane/ethyl acetate).

8 g of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateare obtained in the form of a white solid (yield=60%).

b) Preparation of ethyl3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4′-trifluoromethanesulfonyloxybiphenyl-4-carboxylate

8.8 ml (63 mmol) of triethylamine are added, dropwise, in a three-neckedflask under nitrogen, to 18 g (42 mmol) of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein solution in 250 ml of dichloromethane. The reaction medium is cooledto around 0° C. and then 8.48 ml (50 mmol) of trifluoromethanesulfonicanhydride are added dropwise. The reaction medium is stirred for 3 h at0° C., and is then hydrolyzed, washed with a solution of sodiumbicarbonate and dried over magnesium sulfate. After evaporation of thesolvents, the isolated product is purified by silica gel chromatography(heptane/ethyl acetate=95/5).

24 g of ethyl3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4′-trifluoromethanesulfonyloxybiphenyl-4-carboxylateare obtained in the form of a white powder (yield=100%).

c) Preparation of ethyl4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

6 g (10.7 mmol) of ethyl3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4′-trifluoromethanesulfonyloxybiphenyl-4-carboxylate,0.9 g (21 mmol) of lithium chloride, 1.12 g (1.6 mmol) ofbis(triphenylphosphine)palladium dichloride, 30 ml of dimethylformamideand 3.98 ml (12.8 mmol) of allyl tri-n-butyl tin are introduced into athree-necked flask, under nitrogen in this order.

The reaction mixture is stirred for 12 h at 100° C. The reaction ishydrolyzed with a 1 N solution of hydrochloric acid and then extractedwith ethyl acetate. The organic phases are combined, washed with asaturated aqueous solution of sodium chloride, and dried over magnesiumsulfate. The solvents are evaporated off. The crude obtained in the formof an oil is purified by silica gel chromatography (heptane/ethylacetate: =95/5).

6.1 g of ethyl4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateare obtained in the form of a light yellow oil (yield=100%).

d) Preparation of ethyl4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

0.5 g (1.1 mmol) of ethyl4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateis introduced into 20 ml of tetrahydrofuran, in a three-necked flaskunder nitrogen. This solution is cooled to 0° C. and then 6.6 ml (3.3mmol) of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane intetrahydrofuran are added dropwise. After the addition is complete, thereaction medium is stirred until it returns to ambient temperature. Itis stirred for a further one hour at this temperature, and then againcooled to around 0° C. 3.4 ml (3.4 mmol) of a 1 M solution of sodiumhydroxide are added slowly to the reaction medium, and then 2.8 ml (27.6mmol) of a 30% aqueous hydrogen peroxide solution are added dropwise.After the addition is complete, the reaction medium is stirred whileallowing the temperature to return to ambient temperature. The medium isstirred for 12 h at this temperature, and is then hydrolyzed with asolution of ammonium chloride. The aqueous phase is extracted with ethylacetate and the combined organic phases are washed with water and thendried over magnesium sulfate. The solvents are evaporated off. The crudeobtained is purified by silica gel chromatography (heptane/ethylacetate: 95/5).

300 mg of ethyl4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateare obtained in the form of a colorless oil (yield=58%).

e) Synthesis of4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid

1 ml (1 mmol) of an aqueous solution of sodium hydroxide (1 M) is addedto a solution of 300 mg (0.64 mmol) of ethyl4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein 15 ml of tetrahydrofuran and 1 ml of ethanol. The reaction mixture isstirred for 14 h while heating at 50° C. After the reaction mixture hasreturned to ambient temperature, 2 ml (2 mmol) of a solution ofhydrochloric acid (1 N) are added. The medium is extracted with ethylacetate. The organic phase is washed with water, and then dried overmagnesium sulfate. After evaporation of the solvents, the productobtained is purified by silica gel chromatography (heptane/ethylacetate: =3/2).

230 mg of4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid are obtained (white solid, Mp=203° C., yield=90%).

Example 2 Synthesis of4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid

a) Preparation of ethyl4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

2.84 g (6.3 mmol) of ethyl4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate(prepared according to Example 1, step c)) are introduced, in athree-necked flask under nitrogen, into 15 ml of dichloromethane andthen 1.0 g (7.5 mmol) of N-methylmorpholine N-oxide is added.

2.27 ml (0.18 mmol) of a solution of osmium tetraoxide at 2.5% by weightin isopropanol are added at ambient temperature. The reaction mediumbecomes dark yellow. It is stirred for 3 h at ambient temperature, andis then hydrolyzed and extracted with dichloromethane. The combinedorganic phases are washed with sodium thiosulfate and then dried overmagnesium sulfate. After evaporation of the solvents, the productobtained is purified by silica gel chromatography (heptane/ethylacetate=1/1).

1.92 g of ethyl4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateare obtained in the form of a beige oil (yield=63%).

b) Synthesis of4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid

1 ml (1 mmol) of an aqueous solution of sodium hydroxide (1 M) is addedto a solution of 200 mg (0.41 mmol) of ethyl4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein 5 ml of tetrahydrofuran and 2 ml of ethanol. The reaction mixture isstirred for 48 h while heating at 50° C. After the reaction mixture hasreturned to ambient temperature, 2 ml (2 mmol) of a solution ofhydrochloric acid (1 N) are added. The medium is extracted with ethylacetate. The organic phase is washed with water, and then dried overmagnesium sulfate. After evaporation of the solvents, the productobtained is purified by crystallization from a heptane/diethyl ethermixture. 180 mg of4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid are obtained (beige solid, Mp=145° C., yield=96%).

Example 3 Transactivation Test

Principle of the Test:

The activation of the receptors by an agonist (activator) in HeLa cellsresults in the expression of a reporter gene, luciferase, which, in thepresence of a substrate, generates light. It is thus possible to measurethe activation of the receptors by quantifying the luminescence producedafter incubation of the cells in the presence of a reference antagonist.The activating products displace the antagonist from its site, thusallowing activation of the receptor. The activity is measured byquantifying the increase in the light produced. This measurement makesit possible to determine the activator activity of the compound that canbe used in the invention.

In this study, a constant which is the affinity of the molecule for thereceptor is determined. Since this value can fluctuate according to thebasal activity and the expression of the receptor, it is designatedapparent Kd (KdApp).

In order to determine this constant, “cross curves” of the test product(4′-(3′-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid and4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid), against a reference antagonist otherwise known as referenceligand,4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid, are produced. The test product is used at 10 concentrations andthe reference antagonist at 7 concentrations. In each well (of a 96-wellplate), the cells are in contact with one concentration of the testproduct and one concentration of the reference antagonist.

Measurements are also carried out for the total agonist control,otherwise known as 100% control(4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propenyl]benzoicacid), and the inverse agonist control, otherwise known as 0% control(4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)]-3-oxopropenyl}benzoicacid).

These cross curves make it possible to determine the AC50 values(concentration at which 50% activation of the receptor is observed) ofthe reference ligand at various concentrations of test product. TheseAC50 values are used to calculate the Schild regression by plotting astraight line corresponding to the Schild equation (“Quantitation inreceptor pharmacology” Terry P. Kenakin, Receptors and Channels, 2001,7, 371-385).

In the case of an agonist, the AC50 is calculated by plotting the curveof the product at the concentration of the reference ligand giving 80%activation. The percentage activation which corresponds to the maximumlevel of activity obtained is also measured.

Materials and Method:

The HeLa cell lines used are stable transfectants containing theplasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and RAR (α, β, γ)ER-DBO-puro. These cells are seeded into 96-well plates at a rate of10,000 cells per well in 100 μl of DMEM medium without phenol red andsupplemented with 10% defatted calf serum. The plates are then incubatedat 37° C., 7% CO₂ for 4 hours.

The various dilutions of the test product, of the reference ligand

(4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid), of the 100% control (100 nM4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propenyl]benzoicacid) and of the 0% control (500 nM4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)]-3-oxopropenyl}benzoicacid) are added at a rate of 5 μl per well. The plates are thenincubated for 18 hours at 37° C., 7% CO₂.

The culture medium is removed by turning the plates over, and 1.00 μl ofa 1:1 PBS (phosphate buffered solution)/luciferin mixture are added toeach well. After 5 minutes, the plates are read using the luminescencereader.

Results:

The values of the apparent Kd constants are indicated in the tablebelow. These values are compared to those of the compounds of WO99/10308 having the same activities.

RAR RAR RAR alpha beta gamma Kdapp Kdapp Kdapp (nM) (nM) (nM) Compoundof Example 1 15 2 0.1 Compound of Example 2 60 15 0.5 Compounds of WO99/10308: 3″-Methyl-2′-(5,5,8,8-tetramethyl- 2 1 0.255,6,7,8-tetrahydronaphthalen-2- yl)-[1,1′:4,1″]-tert-phenyl-4″-carboxylic acid (Example 41) 3″-Hydroxy-2′-(5,5,8,8- 2 1 0.25tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-[1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 46)2″-Methoxy-2′-(5,5,8,8- 4 2 0.5 tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)- [1,1′:4,1″]-tert-phenyl-4″- carboxylic acid(Example 44) 2″-Hydroxy-2′-(5,5,8,8- 8 4 1 tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)- [1,1′:4,1″]-tert-phenyl-4″- carboxylic acid(Example 42) 6-[2-(5,5,8,8-Tetramethyl-5,6,7,8- 4 1 1tetrahydronaphthalen-2- yl)biphenyl-4-yl]nicotinic acid (Example 47)2′-(5,5,8,8-Tetramethyl-5,6,7,8- 2 1 1 tetrahydronaphthalen-2-yl)-[1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 14)

The results obtained with4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid and4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid clearly show a better selectivity of these compounds for the RARgamma receptor subtype in comparison with the other two subtypes RARalpha and RAR beta. They also show a better activity and a betterselectivity in comparison with the most active RAR compounds describedin WO 99/10308.

These compounds are therefore selective agonists or activators of theRAR gamma receptor.

Example 4 Examples of Formulations

In this example, various specific formulations based on the compoundsaccording to the invention are illustrated.

A - ORAL ADMINISTRATION: (a) Tablet of 0.2 g:4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.001 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Starch 0.114 gDicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 gMagnesium stearate 0.005 g (b) Oral suspension in 5 ml ampoules:4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.001 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Glycerol 0.500 g70% Sorbitol 0.500 g Sodium saccharinate 0.010 g Methylpara-hydroxybenzoate 0.040 g Flavoring qs Purified water qs 5 ml

B - PARENTERAL ADMINISTRATION: (a) Composition:4′-(2,3-Dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.05%tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Polyethyleneglycol 20% 0.9% NaCl solution qs 100 (b) Injectable cyclodextrincomposition: 4′-(2,3-Dihydroxypropyl)-3′-(5,5,8,8-tetramethyl- 0.1 mg5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acidβ-Cyclodextrin 0.10 g Water for injectable preparation qs 10.00 g

C - TOPICAL ADMINISTRATION: Ointment:4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.300 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Codex whitepetroleum jelly qs 100 g (b) Nonionic water-in-oil cream:4′-(2,3-Dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.100 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Mixture ofemulsive lanolin alcohols, of waxes 39.900 g and of oils (“anhydrouseucerin” marketed by BDF) Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g (c)Lotion: 4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.100 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Polyethyleneglycol (PEG 400) 69.900 g 95% Ethanol 30.000 g

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. The biphenyl compound of formula (I):

in which R is a hydroxyl radical, or salt thereof.
 2. The compound asdefined by claim 1, the same being4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2yl)biphenyl-4-carboxylicacid.
 3. A medicament comprising the compound as defined by claim 1, orsalt thereof.
 4. A pharmaceutical or cosmetic composition, whichcomprises, formulated into a pharmaceutically or cosmetically acceptablecarrier, the compound of formula (I) as defined by claim 1, or saltthereof.
 5. The pharmaceutical or cosmetic composition as defined byclaim 4, formulated for topical administration.
 6. The pharmaceutical orcosmetic composition as defined by claim 4, wherein the amount ofcompound of formula (I) ranges from 0.001% to 3% by weight, relative tothe total weight thereof.
 7. A method for exercising a selective agonistactivity on the RAR gamma receptor, the method comprising contactingsaid receptor with an effective amount of the compound of formula (I) asdefined by claim 1 or salt thereof.
 8. A method for the treatment ofacne or psoriasis, the method comprising administering to an individualin need of such treatment, a thus effective amount of the compound offormula (I) as defined by claim 1 or salt thereof.
 9. A method for thetreatment of acne, the method comprising administering to an individualin need of such treatment, a thus effective amount of a compound offormula (I) as defined by claim 1 or salt thereof.
 10. A method for thetreatment of psoriasis, the method comprising administering to anindividual in need of such treatment, a thus effective amount of acompound of formula (I) as defined by claim 1 or salt thereof.
 11. Aprocess for preparing the compound of formula (I) as defined by claim 1,comprising the following steps: i) conducting a Suzuki reaction betweenthe compound of formula 1

and the compound of formula 2

to produce the compound of formula 3

ii) reacting the compound of formula 3 with triflic anhydride to producethe compound of formula 4

iii) reacting the compound of formula 4 with allyl tri-n-butyl tin toproduce the compound of formula 5

iv) dihydroxylating the allylic double bond of the compound of formula 5to produce the compound of formula 6 in which R is a hydroxyl radical

v) saponifying the ester function of the compound of formula 6 to affordthe compound of formula (I).